Atherosclerosis is a disorder of the large arteries that begins with the accumulation of lipoproteins in the artery wall and develops into lesions. This accumulation is associated with high plasma lipoprotein concentrations, and thus lipoprotein transport into and accumulation in the artery wall has been the focus of intense study. If lipoprotein transport and accumulation in the vessel wall is the key to atherosclerosis, then a good understanding of these processes should explain why different vessels have different susceptibilities to disease and why these susceptibilities vary with conditions such as transmural pressure. In particular, the pulmonary artery (PA) and the large veins such as the inferior vena cava and the saphenous vein are exposed to much lower transmural pressures than the large arteries and are normally resistant to atherosclerosis. But, the PA becomes disease prone under pulmonary hypertension and large veins when exposed to artery pressure. We have developed an endothelial cell-level approach to the transport into and accumulation in the aortic wall, which seem to have vessel-in-dependent features. This proposal extends that approach to a more general venue for a detailed understanding of how the transmural pressure, vessel ultrastructure and endothelial cell turnover influence transport and accumulation in the low-pressure PA and the large vein (inferior vena cava). It does not treat vessel remodeling. The theory aims to model the roles of vessel structure and pressure conditions on the transport processes of lipoproteins in relation to atherosclerosis. The proposed research is designed by combining animal experimentation and theoretical modeling, each guiding the other, to understand these roles. In particular, the theory should be able to explain Tompkins' decade-old profiles of the tracer concentration-vs-depth into the vessel wall that coarser theories less in tune with the vessel's histology could not. It also tests the hypothesis that the kinetics of lipid binding to arterial extra-cellular intimal matrix and accumulation there is vessel independent; vessel dependence would derive solely from the vessel's peculiar transport problem that supplies free LDL to the tissue and its proteoglycan type/amount. The long-term goal is to be able to predict a vessel's lipid accumulation patterns based on its ultrastructure and conditions, e.g., transmural pressure. The hypothesis is that this will correlate with susceptibility to atherosclerosis and, if so, can contribute to an understanding of the effect of blood pressure on atherogenesis in certain vessels. The ultimate goal of the proposed research is to provide information needed for the prevention and treatment of atherosclerosis in humans.